European Patent Application No. 004918 as laid open describes inter alia a process for the production of 17-C-steroid-.alpha.-propionic acid compounds by microbial side chain degradation on 17-C-side chain steroid substrates. In this way, it is possible in particular to produce 3-oxo-pregna-4-ene-20-carboxylic acid (.DELTA.4-BNC) and/or 3-oxo-pregna-1,4-dien-20-carboxylic acid (.DELTA.1,4-BNC). The process uses microorganism defect mutants which give steroid compounds containing the 17-C-.alpha.-propionic acid residue, even in the absence of inhibitors which inhibit degradation of the steroid ring and/or growth. These defect mutants are obtained and grown in accordance with the above-mentioned European Patent Application. A modification of this process is described in earlier European Patent Application No. 0015 308.
The structural formulae of .DELTA.4-BNC and .DELTA.1,4-BNC are as follows: ##STR1## 3-oxo-pregna-4-ene-20-carboxylic acid ##STR2## 3-oxo-pregna-1,4-dien-20-carboxylic acid
German Offenlegungsschrift No. 28 39 033 describes structurally analogous steroid-20-carboxylic acids containing an additional double bond in the 9(11)-position and a process for their production. In particular, one possibility of producing .DELTA.1,4,9(11)-BNC is described therein. U.S. Pat. No. 4,062,880 describes the structurally related .DELTA.4,9(11)-BNC.
The hitherto mentioned BNC-compounds contain a functional group in only the 3-position of the ring system. However, all pharmacologically active corticosteroids contain additional oxygen functions. The 11,17 and 21 positions inter alia are particularly important in this respect. Normally, some of these oxygen functions are chemically introduced, including in particular the 17 and 21 positions.
By contrast, oxidation of the 11-position in steroid compounds is preferably carried out microbially. Several microbial steroid oxidations in the 11-position are described in the specialist literature. In this connection, reference is made to the following publications and to the original Articles quoted therein: F. Drawert "Biosynthese von Hydroxy-Verbindungen (Biosynthesis of Hydroxy Compounds);" Houben-Weyl "Methoden der organischen Chemie" (1978) 6/1d, pages 378-388; T. H. Stoudt, Adv. Appl. Microbial. 2 (1960), pages 190-195; and W. Charney and H. L. Herzog "Microbial Transformations of Steroids" Academic Press (1967), New York, page 29.
The microbial 11-hydroxylation of a variety of steroid compounds and the synthesis products obtained are described in these publications with numerous references to certain microorganism strains, particularly from the class of fungi.
The 11.beta.-hydroxyl or 11-oxo configuration is generally required for strong pharmacological activity. Steroids hydroxylated in the 11.beta.-position are obtained either by using microorganisms strains which introduce a hydroxyl group of the type in question stereoselectively or by using other microorganisms which hydroxylate in the 11.alpha.-position either predominantly or completely stereoselectively. In this case, the 11.beta.-hydroxylated steroids are obtained by chemical oxidation to the 11-ketone in a first step, followed by reduction with a suitable reducing agent. The 11.beta.-hydroxy compound can be formed stereoselectively. So far as the relevant literature on this subsequent chemical transformation is concerned, reference is made, for example, to: L. F. Fieser, M. Fieser "Steroide (Steroids)" Verlag Chemie (Weinheim 1961), 737 et seq., and to the original literature reference cited therein, J. Am. Chem. Soc. 77, 4436 (1955).
The production of .DELTA.4- and/or .DELTA.1,4-BNC compounds containing an oxygen function in the 11-position is described, for example, in German Offenlegungsschrift No. 28 39 033. In this process, the BNC-compounds unsubstituted in the 11-position are microbiologically oxidized in the 11-position under aerobic conditions in an aqueous nutrient medium. The production of 11.alpha.-hydroxy or 11.beta.-hydroxy-1,4-BNC and 11-keto-1,4-BNC is described in particular.
Earlier European Patent Appln. No. 81 100 145.2 describes inter alia the hitherto unreported acid chloride of .DELTA.1,4-BNC and a process for its production. Pregna-1,4-dien-3-one-20-carbonyl chloride (.DELTA.1,4-BNC-chloride), other analogous acid halides of .DELTA.1,4-BNC and corresponding acid halides of .DELTA.4-BNC may be obtained by reacting the free acids with halogenating agents. The reaction is preferably carried out at at most moderately elevated temperatures, in particular, at temperatures not exceeding 15.degree. C., and more especially, at temperatures below 5.degree. C. It is also preferred to use the halogenating agent in a substantially stoichiometric quantity or in only a limited molar excess (up to about 10%). In addition, the reaction is best carried out in an inert solvent, for example, in halogenated hydrocarbons. It is possible in this way selectively to halogenate the 20-carboxyl group to form the corresponding acid chloride group without at the same time initiating any undesirable halogenation in the ring system of the steroid compound.
Analogous processes for the production of similar BNC-halides are the subject of my earlier copending, commonly assigned applications. Thus, U.S. patent application Ser. No. 262,971, filed May 12, 1981, abandoned in favor of its continuation-in-part Ser. No. 423,276, filed Sept. 24, 1982, describes the production of the halides of .DELTA.4,9(11)-BNC which may even contain further double bonds, for example, in the 1(2)-position. U.S. patent application Ser. No. 262,965, filed May 12, 1981, abandoned in favor of its continuation-in-part Ser. No. 407,790, filed Aug. 13, 1982, describes the production of halides, particularly chlorides, of comparable BNC-compounds which, in the 11-position, contain an oxygen function and, in particular, a hydroxyl group or a keto group.